A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

Phase 2

Completed

Conditions: Polycythemia Vera
Primary Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis

Interventions: Biological: RO7490677
Drug: Ruxolitinib

Registration Number: NCT01981850

Lead Sponsor: Hoffmann-La Roche

Brief Summary: RO7490677 is an investigational drug that is being developed for possible use in the treatment of myelofibrosis (MF), a disease in which the bone marrow, which is the organ in the body that makes blood cells, is replaced by fibrosis, or excess scar tissue.

The purpose of this study is to gather information on whether RO7490677 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.

Detailed Description: Stage 1 of this study has completed. Stage 1 was an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of two different dose schedules of RO7490677 in participants with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules receiving either single-agent RO7490677 or RO7490677 in combination with ruxolitinib. Participants were assigned to a weekly or every four week dosing schedule by the investigator.

Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of RO7490677 in participants with PMF and post ET/PV MF. Participants will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of RO7490677. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. Modifications to dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 125

Inclusion Criteria

Participants must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
Participants must voluntarily sign an ICF;
Participants must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF;
At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis;
Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System
A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score;
Participants must not be candidates for ruxolitinib based on EITHER:
1. Platelet count < 50 x 10e9/L, OR
2. Hgb < 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study entry, and be intolerant of or had inadequate response to ruxolitinib;
Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F);
Life expectancy of at least twelve months;
At least four weeks must have elapsed between the last dose of any MF- directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment;
Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;
Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 years or 12 months if >55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception are outlined in the protocol.
Ability to adhere to the study visit schedule and all protocol requirements;
Must have adequate organ function as demonstrated by the following:
- ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF);
- Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF);
- Serum creatinine ≤ 2.5 mg/dL x ULN.

Exclusion Criteria

White blood cell count > 25 x 10e9/L or > 10% peripheral blood blasts;
Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer;
History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months;
Presence of active serious infection;
Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study;
Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection;
Organ transplant recipients other than bone marrow transplant;
Women who are pregnant or lactating.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stage 2: Cohort 3 10mg /kg Every 4 Weeks	RO7490677	Participants will be treated with single agent RO7490677 at a dose of 10 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
Stage 2: Cohort 2 3mg/kg Every 4 Weeks	RO7490677	Participants will be treated with single agent RO7490677 at a dose of 3.0 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
Stage 1: Cohort 2 Every 4 Weeks	RO7490677	Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks	RO7490677	Participants will be treated with single agent RO7490677 at a dose of 0.3 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
Stage 1: Cohort 1 Weekly	RO7490677	Participants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.
Stage 1: Cohort 1 Every 4 Weeks	RO7490677	Paricipants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.
Stage 1: Cohort 2 Weekly	RO7490677	Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.
Stage 1: Cohort 2 Weekly	Ruxolitinib	Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.
Stage 1: Cohort 2 Every 4 Weeks	Ruxolitinib	Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Primary Outcome Measures

Name	Time	Method
Stage 1 Main Phase: Overall Response Rate (ORR)	Up until and including completion of 6 cycles. Each cycle is 28 days.	ORR was defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This was defined as those participants who achieved clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR had at least stable disease (SD) for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease.
Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)	Up until and including completion of 9 cycles. Each cycle is 28 days.	Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria from baseline to any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
Stage 1 Main + Open-Label Extension (OLE): ORR	From cycle 1 day 1 up until cycle 6, day 29 (Main Phase). From cycle 7 day 1 up until study discontinuation or study termination, up to 83 cycles (OLE). Each cycle is 28 days.	ORR was defined as the percent of participants with a response according to the IWG-MRT criteria. This was defined as those participants who achieved CI, PR, or CR at a post-baseline assessment of treatment response OR had at least SD for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease. Participants who achieved a clinical benefit in the main phase had the opportunity to remain on treatment. The determination of ORR in the main phase is outlined in the arms description below. Participants who didn't achieve a benefit had the opportunity to switch to a different dosing schedule in the OLE phase. The determination of ORR in the OLE phase is outlined in the arms descriptions below.
Stage 2 Main + Open-Label Extension (OLE): BMRR	From cycle 1 day 1 up until cycle 9 day 29 (main phase). From cycle 10 day 1 up until study discontinuation or study termination, up to 51 cycles (OLE). Each cycle is 28 days.	Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. Participants in the main phase had the opportunity to remain on treatment (as outlined in the arms description below). Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment and receive PRM-151 10 mg/kg/Q4W (as outlined in the arms description below).

Secondary Outcome Measures

Name	Time	Method
Stage 1 Main Phase: BMRR	Baseline, Weeks 12 and 24	Bone marrow response was defined as a reduction in bone marrow fibrosis score by at least one grade from baseline at anytime during the study.
Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes	Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.	The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. The values reported are the change from baseline scores.
Stage 2 Main Phase: BMRR	Up until and including completion of 9 cycles. Each cycle is 28 days.	Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria at any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.
Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit	Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.	Reduction in bone marrow fibrosis score: Reduction of at least one grade from baseline. Bone marrow fibrosis grades according to WHO criteria (as determined by central adjudication).
Stage 2 Main Phase: Duration of Bone Marrow Improvement	From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.	Duration of response was defined as time from first decrease from baseline \>= 1 grade to time of return to baseline levels.
Stage 2 Main Phase: Hemoglobin Improvement	Up until and including completion of 9 cycles. Each cycle is 28 days.	Hemoglobin improvement was measured by the percent of participants with: Red cell transfusion independence (no transfusions for \>= 12 consecutive weeks) OR 50% reduction in red blood cell (RBC) transfusions for \>= 12 consecutive weeks OR percent of participants with \>= 10 g/L and \>= 20 g/L increase in hemoglobin for \>= 12 consecutive weeks without transfusions (outcome parameter assessed was dependent on baseline hemoglobin/transfusion status).
Stage 2 Main Phase: Platelet Improvement	Up until and including completion of 9 cycles. Each cycle is 28 days.	Platelet improvement was measured by the percent of participants with: Platelet transfusion independence (no transfusions for \>= 12 consecutive weeks) OR 50% reduction in platelets transfusions for \>= 12 consecutive weeks OR doubling of baseline platelet count for \>= 12 consecutive weeks without platelet transfusions OR platelet count \> 50 x 10e9/L for \>=12 consecutive weeks without platelet transfusions OR doubling of baseline platelet count for \>= 12 consecutive weeks without platelet transfusions OR platelet count \> 25 x 10e9/L for \>= 12 consecutive weeks without platelet transfusions (outcome parameter assessed is dependent on baseline platelet status).
Stage 2 Main Phase: Symptom Improvement	Up until and including completion of 9 cycles. Each cycle is 28 days.	Symptom improvement was assessed as the percent of participants with 50% reduction in MPN-SAF TSS from baseline over time. The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable.
Stage 2 Main Phase: Percentage of Participants With Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria	Up until and including completion of 9 cycles. Each cycle is 28 days.	Best Overall Response: (CR, PR, CI), SD and PD according to the IWG-MRT Criteria.

Trial Locations

Locations (23): Radboud University Medical Center
🇳🇱
Nijmegen, Netherlands
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Mayo Clinic Cancer Center
🇺🇸
Phoenix, Arizona, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
University Medical Center RWTH Aachen
🇩🇪
Aachen, Germany
Johannes Wesling Academic Medical Center
🇩🇪
Minden, Germany
Hadassah Medical Centre
🇮🇱
Jerusalem, Israel
Fondazione IRCCS Policlinico San Matteo
🇮🇹
Pavia, Italy
Marche Nord Hospital
🇮🇹
Pesaro, Italy
Guy's and St. Thomas' Hospital
🇬🇧
London, United Kingdom
Stanford Cancer Institute
🇺🇸
Palo Alto, California, United States
University of Maryland Medical Center
🇺🇸
Baltimore, Maryland, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Wake Forest Baptist Medical Center
🇺🇸
Winston-Salem, North Carolina, United States
Mount Sinai Medical Center
🇺🇸
New York, New York, United States
Emory Hospital
🇺🇸
Atlanta, Georgia, United States
Providence Health Care
🇨🇦
Vancouver, British Columbia, Canada
Weill Cornell Medical Center
🇺🇸
New York, New York, United States
The Princess Margaret Cancer Centre
🇨🇦
Toronto, Ontario, Canada
Hospital Saint-Louis
🇫🇷
Paris, France
Meir Medical Centre
🇮🇱
Kfar Saba, Israel
Erasmus Medical Center
🇳🇱
Rotterdam, Zuid Holland, Netherlands